Application of the Hydrogen-Bond-Mediated Aglycone Delivery (HAD) Reaction to the Synthesis of α- and β-Linked...

Controlling stereoselectivity of glycosylation reactions remains one of the central challenges in synthetic carbohydrate chemistry. In this study, we explore the impact of O-picoloyl (Pico) protecting group positioning on the stereoselectivity of glycosylation with 2-azido-2-deoxyglucosyl donors. Three glycosyl donors were designed and synthesized, each bearing the Pico group at a different position (C-3, C-4, or C-6). The glycosyl donor performance was evaluated through H-bond-mediated aglycone delivery (HAD) glycosylation reaction with a series of primary and secondary glycosyl acceptors. All donors exhibited good to high yields across a range of substrates. However, the stereochemical outcome proved highly dependent on the position of the Pico group: 3-Pico and 6-Pico donors were β-gluco selective, whereas 4-Pico donors produced predominantly α-linked products, albeit with moderate selectivity. The performance of the 6-Pico derivative that produced glycosides with complete β-gluco selectivity in all applications, was the most impressive. We then showcased how the 6-Pico donor could be applied to the synthesis of β-linked glycosaminoglycans up to a tetramer. Each glycosylation step proceeded with complete β-selectivity, which opens a viable perspective to synthesizing this type of glycan sequence with glycosyl donors lacking a participating group at C-2.